3, 4-dihydroxy-4&#39;-halogeno chalcones



Patented .iel 28,1953 2 647 148 NITED STATES PATENT OFFICE3,4-DIHYDROXY-4'-HALOGENO CHALCONES Gustav J. Martin and Jay MortonBeiler, Philadelphia, Souren Avakian, Oreland, and Jack N. Moss,Philadelphia, Pa., assignors to The National Drug Company, Philadelphia,Pa., a corporation of Pennsylvania N Drawing. Application July 20, 1951,

Serial No. 237,834

3 Claims. (Cl. 260-590) 1 2 This invention relates to certaintherapeutic refluxed in a steam bath. After three hours the compoundsand more particularly to novel comsolution was cooled, added to 500 g.of ice, acidpositions useful in combatting infectious diseases. ifiedwith hydrochloric acid and filtered. Crys- An especially diiiicultdisease to combat is one tallization from ethyl acetate gave 8 g. of thedecaused by parasitic organisms. Parasites cause sired compound. Thisnew product consisted of a number of diseases in both man and animals,yellow crystals melting at 224-5" 0. and analyzand therapy therefore hasgenerally been noning thus: specific. For instance, the trypanosomes,plas- N er em 12 90 modia and the like are usually treated with arse-(theol) p c n N (fd.) 12.57, 12.58 me and antimony derivatives. Suchmaterials are not only non-specific but they are actually I s e the samemlxture. but a l w ng the solutoxic to the host. Furthermore, infectiouspara- @1011 130 ll at 9 temperature 6 d ys 1nsites rapidly developresistance to them. Stead P heating yielded 2 of the D Odu t- It has nowbeen found that certain substituted y, d1hydroxy =-fl r0 c alcchalcones, which have been newly synthesized, 15 was prepared by addinga Solution of of are highly effective and specific therapetuicp'fiuomacetophenone and of 34'dIhYdIOXY agents for diseases such astrypanosomiasis. hehzaldehyde in 109 Of yl ol 110 These new productsbroadly comprise 3 of 69% KOH solution. The mixture was allowed droxyl hl chamones, t t is t say to stand 18 hours at room temperature and thenpounds havin th general formula; 20 acidified with hydrochloric acid(400 cc. concentrated acid and 1 kg. ice). It was then filtered,water-washed and the desired product crystallized from an ethylacetate-ethyl alcohol mixture. Eleven grams of yellow crystals, melting25 at 219-220 C. were obtained.

Calcd. for ClSHllOZiFZ C, 69.76; H, 4.28. Found:

| The therapeutic value of these novel composi- X 011 tions has beendemonstrated by in vivo experiwherein X is a halogen atom. Asparticularly ments with mice infected with Trypanosoma useful examplesof this new class of substances equiper dum. Twelve of these infectedmice were may be mentioned 3,4-dihydroxy-4-chl0ro chalinjectedsubcutaneously with a saline solution of cone, i. e.3,4-dihydroxy-4-chloro chalcone, sufiicient to O 7 provide a 50 mg. doseper kg. of body weight. A

ll OEFCH group of 10 mice was similarly treated with a dosage of 100 mg.per kg. A third group of 10 mice was fed a diet containing 1% by weightof the new chloro chalcone product. Twenty-two OH mice were infected butgiven no therapy, to protl 11 vide a control. Doses were given daily,and the experiment ran 8 days. All of the controls which died did sowithin the first 6 days. The results and 3,4-dihydroxy-4'-fluorochalcone, i. e. were as follows:

P t 1 a /COH=CH\ Dose Deaths su fs r al Exa iii ation mgJK. S. C... 4/1267 Negative. 100 mg.[K. s. o 3/10 70 D0. OH 1% in diet 0/10 Do.

Controls 20/22 9 F 50 H This class of chalcones is surprisingly and Thegeneral method for preparin S peculiarly specific for infections of theparasitic po s 18 pr y tqreact d hydroxy benztype. They have beendetermined to be ineffective aldehyde Wlth the f d S s d c p in the caseof various bacterial or viral diseases no e- ThuS, e Y ychloro Chal- 55from other sources. Their toxicity to the host cone has been made asfollows: i inconsequential.

A solution of 10 ef 4-ch10r0a0et0pheh0he It is substantially unimportantwhat dosage and 10 of 3,42-dihydr0Xy behzaldehyde in form is chosen.Depending on the wishes of the cc. of ethyl alcohol was added to 150 cc.of 20% doctor and the character of the host, the compotassium hydroxidesolution and the mixture 60 pounds may be given as solids by oralingestion.

3 4 They may be supplied as aqueous solutions, es- 2.3,4-dihydroxy-4-ch1oro chalcone. pecially in isotonic saline solution,and injected 3. 3,4-dihydroxy-4'-fiuoro chalcone. parenterally.Solutions or suspensions may also be administered intravenously,intramuscularly, GUSTAV J. MARTIN. subcutaneously or by any otherdesired method. 5 JAY MORTON BEILER.

As many apparently widely different embodi- SOUREN AVAKIAN. ments ofthis invention may be made without de- JACK N. MOSS. parting from thespirit and scope thereof, this invention is only to be deemed limited bythe R f ences Cited i the e Of this p te Specific Wording of theappended i s- 10 Bradsher et a1., Jour. Am. Chem. 500.," vol.

We clalml 7 pages 3570 (1949).

1. 3,4-dihydroxy-4'-halogeno chalcones.

1. 3,4-DIHYDROXY-4''-HALOGENO CHALCONES,